Graduate Studies

 

Date of Award

12-1-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Biological Sciences

First Advisor

Charles Wood

Second Advisor

Eric Weaver

Abstract

Kaposi sarcoma-associated herpesvirus is the etiological agent of several pathologies including Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Here, we investigated both the tumor microenvironment (TME) in KS lesions as well as plasma from KSHV-infected individuals and how metabolic dysfunction and dysregulated cytokines might have a systemic effect on KS tumorigenesis. Based on previously published KS tumor transcriptomics, one aspect of our investigation involved characterizing cell surface glycoproteins with potential to serve as therapeutic targets against KSHV-infected cells or KS tumors or as biomarkers for disease. Expression patterns of such markers may also suggest the cellular origin of KS tumors. We found that several surface proteins and endothelial lineage markers were overexpressed in KS biopsies compared to uninvolved skin. Colocalization with KSHV LANA was detected using multi-color immunofluorescence in KS tissues, in vitro cultures, and xenografts. The surface glycoproteins KDR, FLT4, UNC5A, ADAM12, and CD34 associated with LANA-positive cells but also perhaps with KSHV uninfected cells or those with KSHV antigen below detection limit in the TME. In KS tumors, most LANA-positive cells co-expressed markers of vascular as well as lymphatic endothelial lineages. This contrasts with normal endothelial tissues and suggests that KSHV tumorigenesis promotes dedifferentiation to a more mesenchymal/progenitor phenotype or that KS results from initial infection of an endothelial (mesenchymal) progenitor cell type. We next studied plasma metabolomics to conduct the first study to explore whether metabolic alterations induced by KSHV/HIV-1 co-infection or KS tumorigenesis could be detected in the plasma of affected subjects and whether different infection and disease states could be distinguished. Results from this preliminary study showed that asymptomatic and symptomatic subject groups exhibited distinct patterns in both polar and non-polar plasma metabolites. These findings suggested dysregulation in amino acid/urea cycle and purine metabolic pathways in KS disease progression, possibly influenced by viral infection. Overall, these findings indicate that more intensive investigation into the temporal patterns of metabolic dysregulation in KSHV infection/HIV co-infection and KS pathogenesis are justified. Overall, the studies herein provided insights into the complex interplay between KSHV, the tumor microenvironment, plasma proteomics, and plasma metabolomics in the context of KS and related diseases.

Comments

Copyright 2023, Sara R. Privatt

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